The Nf1–/+; Trp53–/+cis Mouse Model of Anaplastic Astrocytoma and Secondary Glioblastoma: Dissecting Genetic Susceptibility to Brain Cancer

Abstract

Astrocytic gliomas are the most common primary brain tumors. They include diffuse astrocytomas, mixed oligoastrocytoma, anaplastic astrocytomas, and a subset of glioblastoma multiforme (GBM). Studies on human GBM have shown that upregulation of the Ras signaling pathway and disruption of the p53 checkpoint pathway are central to the formation of these tumors. Although much is now known about the molecular pathways altered in these tumors, they remain largely incurable, primarily due to their diffuse infiltration of the brain and lack of response to chemotherapeutics. The Nf1–/+; Trp53–/+cis mouse model develops diffuse anaplastic astrocytoma and GBM with histology that closely resembles the tumors seen in patients. The incidence of astrocytic gliomas varies in the model depending on the inheritance of mutations from the mother or father and on genetic background. Males and females show different effects, suggesting that sex influences the genetic and epigenetic factors that determine the susceptibility of an individual animal to astrocytic gliomas. This model system, including both genetically engineered mice and derivative cell lines, is useful for understanding the basic biological mechanisms underlying the formation of astrocytic gliomas and for preclinical testing of experimental therapeutics.